Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity.

AIMS: To investigate the pharmacokinetics and safety of tolterodine and tolterodine metabolites after single-and multiple-dose administration in the absence and presence of ketoconazole, an inhibitor of cytochrome P450 (CYP) 3A4, in healthy volunteers with deficient CYP2D6 activity, i.e. poor metabolisers of debrisoquine.

METHODS

Eight healthy volunteers received single oral doses (2 mg) of tolterodine l-tartrate. Following a wash-out period of about 3 months, six of the subjects participated in a multiple-dose (1 mg twice daily) phase of the study. Ketoconazole 200 mg was given once daily for 4-4.5 days during both the single and multiple dose tolterodine administration phases. Blood samples were drawn and the pharmacokinetics of tolterodine and its metabolites were determined.

RESULTS

A decrease (P<0.01) in apparent oral clearance of tolterodine, from 10- 12 l h-1 to 4.3-4.7 l h-1, was obtained during concomitant administration of ketoconazole, yielding at least a two-fold increase in the area under the serum concentration-time curve after single as well as after multiple doses following single dose administration of tolterodine. The mean (+/-s.d.) terminal half-life increased by 50% from 9.7+/-2.7 h to 15+/-5.4 h in the presence of ketoconazole.

CONCLUSIONS

CYP3A4 is the major enzyme involved in the elimination of tolterodine in individuals with deficient CYP2D6 activity (poor metabolisers), since oral clearance of tolterodine decreased by 60% during ketoconazole coadministration. This inhibition resulted in 2.1-fold increase in AUC.